Novel [18F]Fluorine-Based PET Tracers with Polar But Nonbasic Linkers to Image the Fibroblast Activation Protein in the Microenvironment of Tumors

The fibroblast activation protein (FAP) is highly expressed by cancer associated fibroblasts in the microenvironment of tumors. The PET tracer [⁶⁸Ga]Ga-oncoFAP-DOTAGA (1) is clinically used to detect FAP-positive tumors. In order to improve the imaging properties, fluorinated FAP inhibitors 8, 9, 14, and 21 with polar but nonbasic linkers were designed, synthesized, and biologically evaluated. The PEG-based ligand 21 exhibited particularly high FAP inhibitory activity (IC₅₀ = 13 pM), high selectivity toward related dipeptidyl peptidases, very low log D_7.4 value, and high metabolic stability in vitro. Nucleophilic substitution of tosylate 20 led to the PET tracer [¹⁸F]21 in 10.8% radiochemical yield and 97.4% radiochemical purity within a total synthesis time of 119 min [¹⁸F]21 revealed high stability in human and murine serum. In biodistribution studies in CD-1 mice, [¹⁸F]21 showed renal and hepatobiliary elimination. In a mouse xenograft model, considerable accumulation of [¹⁸F]21 in FAP-positive HT1080 tumors was observed.